Mycobacterial infections of the lung remain a serious world-wide problem. Due to a number of number of important cofactors, tuberculosis and other mycobacterial infections are increasing in frequency. New therapeutic options are necessary for multidrug resistant strains of TB as well as other mycobacteria such as M. avium. The longterm objective of this proposal is to develop fundamentally new therapeutic strategies to treat mycobacterial infections. In this proposal we will test the hypothesis that airway delivery of specific nonantibiotic agents will successfully augment attachment, phagocytosis and killing of TB or M. avium by alveolar macrophages (AMs). Since it is known that mycobacteria are rapidly engulfed by AMs and survive and replicate within this intracellular environment, the overall strategy will be to use novel methods of delivery as well as novel therapeutic agents to augment the clearance of mycobacteria by AMs. Two airway delivery methods currently available in our laboratory include: 1) intratracheal delivery using mechanical ventilation, and 2) aerosolization using an ultrasonic nebulizer in line with a "nose-only" device. Using a murine model of immunocompetent BALB/c mice as well as immunodeficient BALB/c mice (SCID and CD4 lymphocyte depleted), we will examine the following specific aims: 1) to determine if surfactant protein A (SP-A) will augment attachment/phagocytosis/killing of TB or M. avium by AMs, 2) to determine if proinflammatory cytokines/agents will augment attachment/phagocytosis/killing of TB or M. avium by AMs, 3) to determine if liposome-encapsulated oligonucleotides can be successfully delivered inside AMs to kill TB or M. avium organisms and 4) to determine if SP-A, proinflammatory cytokine/agents or competitive oligonucleotides are useful therapies for mycobacterial pneumonia. If successful, these studies should result in the development of new therapies and new modes of airway delivery to augment clearance of mycobacteria from the lower respiratory tract.